Since the widespread clinical application of cisplatin as an anticancer drug, bioinorganic chemistry has advanced significantly in creating and designing medicinal metal complexes [[1], [2], [3]]. Platinum-based metal complexes are limited by their toxic side effects, while non‑platinum based metal complexes bring new hope for cancer treatment due to their structural diversity and unique biological properties [[4], [5], [6]]. So far, researchers have designed numerous flexible ligands with transition metal ions to construct complexes with unique structures and properties for multifunctional biological applications [[7], [8], [9], [10], [11], [12]]. Among transition metals, nickel plays a crucial role in biological systems. It not only stimulates haematopoietic function but is also an important component of hydrogenase, urease, and carbon monoxide dehydrogenase, participating in the body's metabolic processes [[13], [14], [15]]. Up to now, different Ni(II) complexes have been synthesized and demonstrated significant inhibitory effects on various of tumor cell lines up to date[[16], [17], [18]].

Schiff bases are a class of organic compounds containing imine or methylimine characteristic groups (-RC=N-) by condensation of amines and active carbonyl groups [[19], [20], [21]]. Its chemical properties and biological activity can be managed by introducing versatile substituents of amines and carbonyl compounds [[22], [23]]. In recent study, the Schiff bases containing 2-amino phenol-derived moties displayed particular anticancer biological properties [24]. In addition, the attachment of halogen atoms (F/Cl/Br) on the benzene ring not only helps to reduce structural symmetry, lower melting point, and improve solubility, but also significantly enhances the lipid solubility and cell membrane penetration ability of the compound [[25], [26], [27]]. Till now, numerous of halogen-substituted Schiff base transition metal complexes have been synthesized and displayed strong cytotoxicity on some tumor cell lines in many recent studies [[28], [29], [30]].

In the present study, the anticancer activities of metal complexes derived from 2-aminophenol-based Schiff bases and their halogen-substituted Schiff base Ni(II) complexes has been rarely reported. In our previous study, a tridentate 5-bromosalicylaldehyde-2-aminophenol Schiff base Ni(II) complex was prepared and exhibited significant anticancer activity against SMMC-7721 and CNE-2Z cells. The findings of this research indicate that it is worth further study. In this paper, six polyhalogenated 2-aminophenol Schiff base derivatives Ni(II) complexes were synthesized, namely [Ni4L14(CH3CH2OH)4] (complex C1), [Ni4L24(CH3CH2OH)4]·CH3CH2OH (complex C2), [Ni4L34(CH3CH2OH)4]·CH3CH2OH (complex C3), [Ni4L44(CH3CH2OH)4] (complex C4), [Ni4L54(CH3CH2OH)4] (complex C5) and [Ni4L64(CH3CH2OH)4] (complex C6). Their relationship between cubane structures and their anticancer activities among these polyhalogenated Ni(II) complexes were studied. The cytotoxicity effects of ligands and their metal complexes on tumor cells were determined and tumor cell migration, apoptosis, cycle, ROS, mitochondrial membrane potential and mechanism of apoptosis pathway were also investigated. Furthermore, the anti-tumor efficacy and potential toxicity to organ function of C5 complex was evaluated in vivo.